Immunization against methamphetamine (MA) is potentially valuable in assisting patients in stopping their abuse. Vaccines against both nicotine and cocaine have been promising in both animal and human studies. Immunotherapeutic approaches to MA addiction also appear promising, but much work is needed to design a MA vaccine that induces high levels of specific antibody. Recent discoveries about regulatory cytokine and chemokine networks and innate immune system toll receptor signaling has opened the door to new ways to regulate immune responses to foreign antigens. We will use these advances in immunological adjuvants and carrier proteins to make a safe and effective MA vaccine. Our Preliminary Results with a new MA vaccine show substantial antibody levels and effects on locomotor activity, but indicate that the carrier protein and adjuvant will make a critical difference in efficacy. We will synthesize a panel of conjugate MA vaccines using different conjugates and different immunological carriers. Four carriers will be compared: Tetanus toxoid, neisseria meningitidis outer membrane protein (OMPC), cholera toxin B and a new lipopeptide based, self-adjuvanting vaccine carrier. In addition, a panel of adjuvants will be examined, carefully selected to complement the biological activity of the selected carrier. These adjuvants include CpG oligonucleotides, MPL, and a squalene-based adjuvant;CFA and alum will be included as controls. Outcomes will be the quantity, quality, and persistence of the antibody response in rodent models as well as inhibition of MA-induced locomotor activity. Based on these data, a clinical candidate and 2 back-ups will be selected and characterized in more detail in preparation for an IND filing. The ability of the vaccine to alter MA pharmacokinetics and metabolism will be assessed, as well as inhibition of reinstatement of MA self-administration. Finally, material suitable for use in a Phase I clinical trial will be manufactured and formal toxicology testing will be completed. At the completion of the funding period, we anticipate filing an IND and commencing clinical testing of a MA vaccine. The key investigators in this application have been successfully collaborating at Baylor for the last two years. Dr. Thomas Kosten has worked with our consultant Dr. Fox for over 10 years developing a cocaine vaccine from pre-clinical concept to successful clinical trials. Dr.Therese Kosten is a leading expert in animal models of stimulant abuse. Drs. Rossen, Baughn and Orson have extensive experience in immunology, and Drs. Orson and Kinsey have been working on the development of DMA vaccines. Our group's combined experience is ideally positioned to get a vaccine quickly into phase 1 human studies.